Unraveling the genome biophysics puzzle

BPJ_112_3.c1.inddWhile digitizing the human genome is one of the recent major scientific achievements, unraveling genome structure and, more importantly, structure–function relationships has been a major preoccupation for many scientific teams worldwide. Indeed, the understanding of structure from the DNA level to nucleosomes, chromatin fibers, genes, and chromosomes holds the key to interpreting many of the associated genome functions from DNA repair and duplication to gene transcription.

To celebrate the anniversary of Biophysical Journal‘s newest section Nucleic Acids and Genome Biophysics, we present this Special Issue devoted to Genome Biophysics.

The cover image for this issue conveys the excitement in the field, as many techniques are being developed and applied by both experimentalists and modelers to decipher aspects of the genome puzzle. Specifically, the cover image highlights the genome puzzle from multiple scales and viewpoints. The illustration, created by G. Bascom and T. Schlick, features images from the contributions by A. Onufriev and colleagues on partially assembled nucleosomes (left top puzzle piece), B. Zhang and P. Wolynes on chromosomal domains (right bottom puzzle piece), and G. Bascom and T. Schlick on looping networks in fibers and genes (central image and background fibers).

We hope BJ readers will enjoy the excellent contributions in this issue that reflect an exciting range of topics, as well as the breadth and depth of this fascinating subject.

– Tamar Schlick

Eat like a local in New Orleans!

We asked 61st Annual Meeting attendees and Biophysical Society members who live in New Orleans for their favorite places to eat and the attractions you shouldn’t miss. See their recommendations below!


The Ruby Slipper Cafe
139 South Cortez Street
Monday-Friday 7am – 2pm
Saturday & Sunday 7am – 3pm

Willa Jean
611 O’Keefe Avenue
Daily 7am – 9pm

Manhattan Jack
4930 Prytania Street
Daily 6:30am – 6pm

Mother’s Restaurant
401 Poydras Street
Daily 7am – 10pm
“Can be busy but they turn it around quickly. Good southern breakfast.”


Landry’s Seafood
8000 Lakeshore Drive
Sunday-Thursday 11am – 9:30pm
Friday-Saturday 11am – 10:30pm

1330 Prytania Street
Monday-Friday 11am – 10pm
Saturday & Sunday 10am – 10pm
“Vegan cuisine.”

Cochon Butcher
930 Tchoupitoulas Street
Monday-Thursday 10am – 10pm
Friday-Saturday 10am – 11pm
Sunday 10am – 4pm
“Everyone will recommend this place, but it is a MUST. Gets very busy, so be flexible.”

St. James Cheese Company
641 Tchoupitoulas Street
Monday-Thursday 11am – 7pm
Friday-Saturday 11am – 9pm
Closed Sunday

Central Grocery & Deli
923 Decatur Street
Daily 9am – 5pm
“If you’ve got time, Central Grocery in the French Quarter for a muffaletta is a fixture.”


Doris Metropolitan
620 Chartres Street
Lunch: Friday-Sunday 12 noon – 2:30pm
Dinner: Daily 5:30pm – 10:30pm

Marcello’s Restaurant & Wine Bar
715 St. Charles Avenue
Monday-Friday 11:30am – 10pm
Saturday 5pm – 10pm
Closed Sunday

625 Chartres Street
Dinner: Monday-Thursday 5:30pm – 11pm
Friday-Saturday 5:30pm – 12 midnight
Sunday 5:30pm – 10pm
Brunch: Friday-Sunday 10:30am – 2:30pm

Paladar 511
511 Marigny Street
Dinner: Wednesday-Monday 5:30pm – 10pm
Brunch: Saturday & Sunday 10am – 2pm

Peche Seafood Grill
800 Magazine Street
Monday-Thursday 11am – 10pm
Friday-Saturday 11am – 11pm
Closed Sunday

1330 Prytania Street
Monday-Friday 11am – 10pm
Saturday & Sunday 10am – 10pm
“Vegan cuisine”

Emeril’s New Orleans
800 Tchoupitoulas Street
Lunch: Monday-Friday 11:30am – 2pm
Dinner: Daily 6pm – 10pm
“A classic treat, and while pricey, less expensive than many high end NOLA restaurants.”

Palace Café
605 Canal Street
Breakfast: Monday-Friday 8am – 11am
Lunch: Monday-Friday 11:30am – 2:30pm
Dinner: Daily 5:30pm – til
Brunch: Saturday & Sunday 10:30am – 2:30pm
“The little brother of Commander’s Palace and is good at accommodating groups with notice.”

Budget Eats

Stein’s Market and Deli
2207 Magazine Street
Tuesday-Friday 7am – 7pm
Saturday & Sunday 9am – 5pm
Closed Monday

Central Grocery & Deli
923 Decatur Street
Daily 9am – 5pm
“If you’ve got time, Central Grocery in the French Quarter for a muffaletta is a fixture.”

Felipe’s Mexican Taqueria
301 N. Peters Street
Sunday-Tuesday, Thursday 11am – 11pm
Wednesday 11am – 1am
Friday & Saturday 11am – 2am

The Company Burger
Girod Street at Rampart Street
Daily 11am – 10pm

Verti Marte
1201 Royal Street
Daily 24 hours

Dat Dog
601 Frenchmen Street
Sunday-Tuesday 11am – 12am
Friday & Saturday 11am – 3am

Mint Modern Vietnamese
5100 Freret Street
Sunday, Tuesday-Thursday 11am – 9pm
Friday & Saturday 11am – 10pm
Closed Monday

Coop’s Place
1109 Decatur Street
Daily 11am – til
“Be ready to wait in a line, but there’s a line for a reason.”

Can’t Miss Attractions

City Park & Sculpture Garden
1 Palm Drive
Large urban park featuring botanical gardens, open-air sculpture garden, and antique wooden carousel.

Café du Monde
800 Decatur Street
Daily 24 hours
Famous coffee and beignets

Lake Pontchartrain

Frenchmen Street
The live music capital of New Orleans

Royal Street
Epicenter of local art

Magazine Street
Shopping, architecture, and museums

St. Louis Cathedral
615 Pere Antoine Alley
Historic church

Lafayette Cemetery No. 1
Washington Avenue & Prytania Street
Monday-Friday 7am – 2:30pm
Saturday 7am – 12 noon
Historic cemetery with above ground crypts

Krewe de Vieux parade
French Quarter
Saturday, February 11, 6:30pm
“It is the kickoff of the Carnival season in NOLA and the only parade that gets to go through the French Quarter. Not for the faint of heart.”

NOLA Brewery
3001 Tchoupitoulas Street
Daily 8am – 5pm

Hot Tin Rooftop Bar
in the Pontchartrain Hotel
2031 St. Charles Avenue
Monday-Thursday 4pm – 12 midnight
Friday & Saturday 2pm – 2am
Sunday 2pm – 12 midnight
“The recently renovated Pontchartrain Hotel was a historical hangout for the likes of Frank Sinatra, Ernest Hemingway, and Tennessee Williams. The new rooftop bar offers one of the best views of the city.”

Three Coexisting Phases of Lipid Membranes

BPJ_112_2.c1.inddWhile there has been a large amount of research into the phase behavior of lipid membranes in the past decade driven by the biological relevance of ordered micro-domains (often termed “lipid-rafts”), images of three coexisting phases are very rare. Researchers have difficulties preparing samples with a high proportion of ordered phase, and finding reliable methods to sufficiently discriminate the phases as fluorescent dyes often prefer one phase and are excluded from the remaining two. The cover image of the January 24th issue of the Biophysical Journal shows a collection of atomic force micrographs (AFM) exhibiting three-phase coexistence in a model cell membrane under water.

Three phases are found in lipid compositions. They lie in a narrow triangle below the more commonly studied two-phase micro-domain region, which contains the liquid disordered (Ld – yellow/red) and liquid ordered (Lo – magenta) phases, together with a gel phase (Lb – blue/green). Each phase has a different degree of chain packing order leading to varying depths. A surprising and counterintuitive finding of this study is that the gel phase, while definitely solid, is more disordered and slightly lower in height than Lo. It is also structurally very weak. This is explained by the small but significant quantity of cholesterol that disrupts the ordered solid phase, while being insufficient to form the Lo phase. Relative proportions of the three phases are governed by their position in the three-phase triangle. Domain morphology is controlled by the mechanism of phase separation. We observed examples of both spinodal and nucleated domains of each phase, and in some cases both mechanisms in the same image An example of this can be seen in the cover image where a nucleated gel phase (green) is surrounded by a percolated Lo/Ld  structure (yellow/magenta). Another interesting finding was the signature of a radially varying composition across the nucleated gel domains, reflecting the kinetically trapped solid state in the process of separating from a compositionally varying melt. This effect has been commonly observed in metallurgy, but not in lipids.

Each image was produced within the standard AFM analysis software, Bruker Nanoscope v1.5. Manual coloring in Photoshop has not been used, rather a standard color look-up table (No 9) is mapped directly to the topography data. The contrast was adjusted so that the lowest phase is on the yellow/red transition, and the highest phase is magenta, resulting in a blue/green middle phase. A problem with this approach is the tiny 0.6 nm difference in height between the highest and lowest phases, which calls for accurate levelling to remove image bowing artefacts common in AFM, provide defined peaks in the depth histogram, and  a uniform color across each phase. This task was made even more painstaking by the presence of three phases interfering with the thresholding and masking approach normally used. The final composite was created simply in Powerpoint.

Our work is part of an EPSRC (Engineering and Physical Sciences Research Council) Program entitled CAPiTALS, which is based around the fundamental understanding of the physics governing lipid membrane curvature, asymmetry, and patterning, and the technological uses arising from this new knowledge.

–  Simon Connell, Anders Aufderhorst-Roberts, Udayan Chandra.

Computational Microscopy: Using Simulations to Decode Infrared Vibrations

BPJ_112_1.c1.inddHeterotrimeric G-proteins are molecular switches that are omnipresent in animal and plant cells. They maintain central physiological processes such as vision, scent, or blood pressure regulation. The signal is determined by a small molecule, Guanosine triphosphate (GTP).  GTP binds to the heterotrimeric protein and thereby switches the signal “on.” The off-switch is maintained by hydrolysis of GTP to GDP and a phosphate moiety.

This central molecular reaction has beenthe focus of research for dozens of years, as the mechanism is highly conserved and leads to a plethora of diseases when disturbed, including cancer.

The cover image for the January 10 issue of the Biophysical Journal shows the GTP molecule bound to the active site of Gi1, one of three subunits of heterotrimeric G-proteins. The image was created using the program Blender. The configuration was obtained from coupled quantum mechanics and molecular dynamics simulations of the protein crystal structure. We used these simulations to obtain a structural interpretation of infrared spectroscopy measurements of the protein. Although infrared spectroscopy yields millisecond temporal and sub-Ångstrom spatial resolution, this information is encoded into infrared spectra that can be hard to interpret. However, a figure like the cover image can help this become easier to understand. By combining simulations with experiments one can use the computer as a microscope with subatomic resolution and directly observe structural and electronic changes. We benchmarked this setup by introducing point mutations at the active site (indicated as sticks in the picture) and comparing experimental and computational spectral changes that were found to be in agreement.

Further simulations elucidated details about the Mg2+ cofactor in the active site (green sphere) and about catalysis of GTP hydrolysis by heterotrimeric G-proteins that can be found in our article.

-Daniel Mann, Udo Höweler, Carsten Kötting and Klaus Gerwert

Get to Know: Bert Tanner, BPS Early Careers Committee Chair

We recently spoke with BPS Early Careers Committee Chair Bert Tanner, Washington State University, about his research, his time on the committee, and the years he spent as a gymnast.

tanner-bertWhat is your current position & area of research?

Assistant Professor, Department of Integrative Physiology and Neuroscience, Washington State University

I study muscle biology and teach physiology to undergraduate, graduate, and veterinary students. Research studies within my laboratory focus on normal, mutated, and diseased proteins that influence muscle contraction. We often integrate mathematical modeling, computational simulations, biochemical assays, and biophysical system-analysis to investigate complex network behavior among muscle proteins. We use these findings to describe and illustrate molecular mechanisms of contraction that underlie muscle function at the cellular and tissue levels.

What drew you to a career as a biophysicist?

I studied Physics as an undergraduate student at University of Utah. The last couple years of my undergraduate studies I got the opportunity to further explore bioengineering and computer science, and I participated in a summer research experiences learning about computational biology, remote sensing, and environmental biophysics. Through these experiences, I became increasingly interested at using mathematics, physics, and computation to better understand and describe biological processes. Through a series of injuries, I started learning more about physiology and became increasingly curious about different applications where mathematical modeling could help illustrate complicated, dynamic processes at the molecular, cellular, and organismal levels.  This led me back to graduate school, where I ultimately began studying muscle biophysics.

What do you find unique or special about BPS? What have you enjoyed about serving on the Early Careers Committee?

I love the rigor, diversity, and plasticity of the Biophysical Society, as well as the annual Biophysical Society meeting.  I’ve been attending and presenting at the national meeting since 2004, and I am really impressed by the high-quality science and constructive engagement of many society members—many of whom have become great friends and colleagues over the years. I also really appreciate the strong commitment to training young scientists in a rigorous, difficult field that is demonstrated by the BPS and its engaged membership. I enjoy being a member of the Early Careers Committee because it is a platform that enables education and programming for early career biophysicists via the newsletters, society webpage and blog posts, and annual meeting events.  These early career biophysicists are among the best and the brightest minds in the world, and our committee feels it is critical to help them learn about the myriad career paths where their skills will make an impact: academia, industry, small business, national laboratories, science writing and education, public policy, etc.

Who do you admire and why?

I admire many people from many different walks of life, but I often think most of the people that have impacted my education in a positive way. This includes a handful of teachers from elementary, middle school, and high school, all of whom made a really big impact on my thinking and career choices. Just like the impact these teachers made on me, other teachers work tirelessly to educate students each day; the well-being of our society greatly benefits from their efforts.  A second tier of people that I really admire are the approachable, engaging, unselfish, and constructively-critical mentors or colleagues that I get to interact with each year.  These people inspire me to try and do my best each day, and to treat people kindly.


What do you like to do, aside from science?

I love the outdoors and to exercise. When I can pair these two up, it is even better.  My favorite hobby is skiing, just being out in the snow and gliding down the mountain, trail, or path is fantastic.  The past few years I’ve spent all my spare skiing-time on the ‘magic carpet’ teaching my son how to ski.  He is 5 now, and getting pretty good at the ‘blue squares’.  On our last ski day in Spring of 2016, my daughter (then about 18 months old) even skied by herself for about 60-100 feet.  She loves skiing and spent most of her first couple seasons skiing in a backpack on my back. I cannot wait to watch her keeping up with her big brother soon.

What is your favorite thing about living in Washington?

The diversity of the outdoor activities.  My family and I get to live in a small town and I get to work at a Pac-12 university with wonderful colleagues and great resources to pursue my research.  However, we are only 30 minutes to 2.5 hours away from world-class white water rivers, camping, hiking, backpacking, and pretty good skiing.  This accessibility to nature, and the diversity of options is really special to me and my family.

What is something BPS members would be surprised to learn about you?

I was a gymnast until age 18.  I loved it, but it took a lot of time and I decided not to pursue it as a collegiate athlete.  However, it was pretty fun watching some of the fellow gymnasts that I’d trained with, and competed against as I grew up, perform in the Olympics over the past 15-16 years.

Do you have a non-science-related recommendation you’d like to share (book, movie, TV show, etc.)?

The recent Zootopia movie has a classic and wonderfully painful scene with sloths running the DMV.  For a quick laugh (2-3 min segment) you should check it out on YouTube.

What drives immune cells to engulf pathogens?

BPJ_111_12.c1.inddMacrophages and neutrophils (phagocytes) are the front-line defenders in your body’s immune system. They seek out, ingest, and destroy pathogens and other debris through a process called phagocytosis.  Typically, phagocytosis is initiated when receptors on the immune cell surface bind to ligands which have coated a pathogen particle. Once the cell’s receptors have found their target ligands, they initiate a chemical cascade within the cell which recruits the biochemical machinery necessary to drive the cell to envelop its target, forming a vacuole in which the pathogen can be degraded.

On a small scale, nearly every cell type in your body internalizes nutrients and various signals through a similar engulfment process called endocytosis What makes immune cells and phagocytosis unique is the relative size of the internalized particle. During endocytosis, cells internalize small objects, typically no larger than 100 nanometers, a fraction of the cell’s size (usually 10-30 micrometers). However, during phagocytosis, immune cells need to be able to internalize very large particles such as bacteria, which could be several microns long, and debris like dead cells, which could be larger than the immune cell itself.

Phagocytes accomplish this seemingly heroic feat by leveraging the biomechanical machinery typically involved with cellular migration, specifically the actin cytoskeleton and myosin molecular motors. Once phagocytosis has been initiated, actin monomers within the cell begin to polymerize near the location of the bound particle. As the polymerized network forms, it pushes the cell’s membrane around the particle, forming what is called a phagocytic cup. Interestingly, as a particle is internalized, the leading edge of the phagocytic cup constricts, pinching down on the particle.

Earlier studies have shown that actin tends to accumulate in a dense ring at the point of constriction. Unfortunately, due to limitations of the microscopy techniques available at the time, the precise structural organization of actin filaments within this ring could not be resolved. Consequently, exactly how the actin ring facilitates constriction remained elusive.

Using super-resolution fluorescent imaging (Structured Illumination Microscopy) we sought to illuminate how actin is reorganized during phagocytosis, with the goal of providing insight as to how phagocytes constrict around their targets.  One of the challenges in using microscopy to study phagocytosis is that particle internalization is three-dimensional, yet nearly all microscopy techniques are inherently two-dimensional. To side-step this issue, we turned to a planar technique called Frustrated Phagocytosis. Instead of presenting immune cells with pathogen particles, we deposited cells onto glass coverslips functionalized with antibodies. When the immune cells contact the surface, they perceive it as a giant pathogen and begin to flatten and spread as if trying to phagocytose the entire plane, yielding an unfolded view of what’s happening at the cell-target interface.

The cover image in the December 20th issue of the Biophysical Journal shows several macrophage cells at various stages of the frustrated phagocytic process. In the image, each cell’s actin cytoskeleton is shown in green (using Atto488-phalloidin) and the nuclei are shown in blue (using DAPI). During the early stages of phagocytosis (top left), actin polymerizes at the leading edge of the cell, forming a dense zone. This is similar to the structure formed at the leading edge of migrating cells. As actin polymerizes at the edge, it pushes the membrane outward causing the cell to spread. As the cell nears its maximum contact area, the actin zone begins to dissociate (top center) and actin-filaments throughout the body of the cell bundle to form fibers (middle right). As the cell enters the later stages of phagocytosis those bundles reorient, surrounding the perimeter of the cell (bottom center and middle left). With actin bundles surrounding the cell, myosin motor proteins exert tension between adjacent bundles. This tension causes the network to contract, forcing the cell to pinch down on the substrate. For frustrated phagocytosis, this constriction drives the cell to retract from the surface, leaving fragments of actin and tethered membrane in its trail (spinney protrusions around bottom center and middle left cells).

The mechanism that triggers the bundles to form and reorganize around the cell perimeter remains a mystery; although, there is mounting evidence that mechanical factors such as the cell’s membrane tension are involved in signaling transitions to late-stage phagocytic behavior.  These images, along with other studies of phagocyte mechanics, illustrate the robust and dynamical processes that unfold when immune cells carry out their essential task of clearing debris and eliminating pathogens.

– Wenbin Wei, Patrick Chang, Jan-Simon Toro, Ruth Fogg Beach, Dwight Chambers, Karen Porter, Doyeon Koo, Jennifer Curtis, Daniel Kovari

Probing Water and DMSO near Lipid Membrane Surfaces

BPJ_111_11.c1.inddDimethyl sulfoxide (DMSO) is a powerful anti-freezing agent and has been used in biology as a cryoprotectant of cells. Thanks to a series of experiments and computer simulations  bulk properties of DMSO solution are reasonably well understood, yet the effects of DMSO on water molecules near lipid membrane surfaces, which are more relevant for elucidating the underlying physical chemistry of DMSO as a cryoprotectant, still remain elusive.

The consensus from a number of different experiments is that DMSO dehydrates phospholipid bilayer surfaces, which our study confirms. However, the DMSO-enhanced water diffusivity at solvent-bilayer interfaces, was not confirmed in our simulations. In order to resolve this discrepancy, we explicitly modeled Tempo-PC by appending Tempos to a few choline groups and conducted simulations and analyses.

Our cover image for the December 6th Issue of the Biophysical Journal depicts a snapshot from the molecular dynamics simulation of POPC phospholipid bilayer in 7.5 mol% DMSO solution. The lipid tails are rendered in grey, and the regions corresponding to phosphatidylcholine head groups are depicted in pale blue. Four Tempo-PCs, in the upper and lower leaflets are highlighted with the tail domain in yellow and the Tempo appended to the choline group in blue. Of particular note is that in contrast to the original intent of Overhauser Dynamic Nuclear Polarization (ODNP) measurements using Tempo-PC lipids to probe the surface water dynamics, the Tempo moieties are predominantly equilibrated at 8 − 10 Å below the solvent-bilayer interface, probing the water dynamics in the interior of bilayer. The water and DMSO molecules around the Tempo moieties are depicted in stick and surface representations, respectively. The inset magnifies the snapshot of water and DMSO molecules around Tempo. The image was produced using the molecular visualization system, PyMOL.

DMSO deposited beneath the PC head group, where Tempo moieties are equilibrated, increases the area per lipid slightly, and hence water diffusion probed by Tempo is detected to increase with increasing DMSO. Our study suggests that the experimentally detected signal of water using Tempo, stems from the interior of lipid bilayers, not from the interface. The only viable tool for the direct probe of water dynamics on biological surfaces at present is ODNP measurements using a Tempo spin label. Given its significance, the equilibrated location of Tempo moiety in lipid bilayers revealed here calls for adequate interpretation of data and careful re-evaluation of the technique.

—Yuno Lee, Philip A. Pincus, Changbong Hyeon